Center for Alzheimer's and Neurodegenerative Diseases, Peter O'Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Structure. 2023 Sep 7;31(9):1025-1037.e4. doi: 10.1016/j.str.2023.05.020. Epub 2023 Jun 21.
Assembly of tau into beta-sheet-rich amyloids dictates the pathology of a diversity of diseases. Lysine acetylation has been proposed to drive tau amyloid assembly, but no direct mechanism has emerged. Using tau fragments, we identify patterns of acetylation that flank amyloidogenic motifs on the tau fragments that promote rapid fibril assembly. We determined a 3.9 Å cryo-EM amyloid fibril structure assembled from an acetylated tau fragment uncovering how lysine acetylation can mediate gain-of-function interactions. Comparison of the structure to an ex vivo tauopathy fibril reveals regions of structural similarity. Finally, we show that fibrils encoding disease-associated patterns of acetylation are active in cell-based tau aggregation assays. Our data uncover the dual role of lysine residues in limiting tau aggregation while their acetylation leads to stabilizing pro-aggregation interactions. Design of tau sequence with specific acetylation patterns may lead to controllable tau aggregation to direct folding of tau into distinct amyloid folds.
tau 聚集成β-片层丰富的淀粉样纤维决定了多种疾病的病理学。赖氨酸乙酰化被认为可以驱动 tau 淀粉样纤维的组装，但目前还没有出现直接的机制。我们使用 tau 片段，确定了在促进快速纤维组装的 tau 片段上淀粉样生成基序侧翼的乙酰化模式。我们从乙酰化 tau 片段组装出了一个 3.9Å 的冷冻电镜淀粉样纤维结构，揭示了赖氨酸乙酰化如何介导获得功能的相互作用。将该结构与体外 tau 病纤维进行比较，揭示了结构相似的区域。最后，我们表明，编码与疾病相关的乙酰化模式的纤维在基于细胞的 tau 聚集测定中具有活性。我们的数据揭示了赖氨酸残基在限制 tau 聚集中的双重作用，而它们的乙酰化导致稳定的促聚集相互作用。具有特定乙酰化模式的 tau 序列的设计可能导致可控的 tau 聚集，从而将 tau 折叠成不同的淀粉样纤维折叠。
